Systematic Functional Interrogation of Neurodevelopmental Disorder Risk Variants

The study used MPRA to test 727 neurodevelopmental disorder-associated non-coding variants in human neural progenitor cells and identified 38 expression-modulating variants (emVars) with regulatory activity. These emVars were predicted to alter transcription factor binding motifs. Using eQTL, ABC models, and CROP-seq perturbation in human stem cell-derived neurons, the authors mapped variants to candidate target genes and found enrichment in developmentally regulated programs including neuronal connectivity, synaptic function, and mitochondrial biology.